Binding characteristics of dialkyl phthalates for the estrogen receptor

Abstract

Dialkyl phthalates have been suggested to function as xenoestrogen. To explore the structural essentials, a series of ring and alkyl-chain isomers of dialkyl phthalates C6H4(COOCnHm)2 were examined for their ability to displace [3H]17beta-estradiol in the recombinant human estrogen receptor expressed on Sf9 vaculovirus. Compounds with an alkyl chain of more than C3 (n = 3) exhibited a distinct full receptor binding in a dose-dependent manner. When the ring isomers of C3-diallyl (-CH2-CH=CH2) derivatives, namely diallyl phthalate, diallyl isophthalate, and diallyl terephthalate, were examined, the ortho isomer of diallyl phthalate was most potent to bind to the estrogen receptor. The interaction with the estrogen receptor was optimized with dibutyl phthalates of C4. The conformational studies by 1H-NMR measurements and ab initio molecular orbital calculations have suggested that the structure mimics the interface of steroid A and B/C rings of 17beta-estradiol. Dicyclohexyl phthalate bound to the estrogen receptor with a biphasic binding curve, suggesting the compound discriminates two different receptor conformations.